SUMMARY/ABSTRACT Bullouspemphigoidisanautoimmunedisordercharacterizedbytheemergenceoflarge,fluid-filled blistersontheskinofaffectedpatients.ItiscausedbypathogenicantibodiesthattargetBP180,acomponent ofthehemidesmosomesthatattachbasalkeratinocytestothebasementmembraneoftheepidermis.The antibodiespromoteinflammationandneutrophilrecruitment,leadingtothedestructionofhemidesmosomes andseparationoftheepidermisfromthedermis.Bullouspemphigoidisthemostcommonblistering autoimmunedisorderoftheskin,and10.8%ofpatientsintheUnitedStatesdiewithinoneyearofdiagnosis. Eveninpatientssuccessfullytreatedforbullouspemphigoid,recurrenceiscommon.Thus,noveltherapeutics tobettertreatandpreventrecurrenceofbullouspemphigoidareneeded. OurpreliminarydatashowsthattheNLRP3inflammasomepathwayanditsendproduct,the inflammatorycytokineIL-1b?,arerequiredforneutrophilrecruitmentandblisterformationinawell-established mousemodelofbullouspemphigoid.Similarly,weobservedthatmicedeficientinthekeratinocyte-specific proteingasderminAhadsignificantlylowerlevelsofIL-1b?withintheskinandwereresistanttoblister formation.GasderminAisamemberofafamilyofproteinsthatincludesgasderminD,whichwasrecently showntomediateIL-1b?releaseandlyticcelldeathdownstreamofinflammasomeactivationinimmunecells. Therefore,wehypothesizethatgasderminAsimilarlyactsdownstreamofinflammasomeactivationwithin keratinocytestopromoteinflammationoftheskinandbullouspemphigoidpathology. InAIM1,wewilldetermineinwhichcelltypestheNLRP3inflammasomeisactivatedinthemouse modelofbullouspemphigoidusingbonemarrowtransplantsandcelltype-specificIL-1b?knockouts,andwewill assesstheroleofterminalcomponentsofcomplementinactivatingNLRP3usingmicedeficientinmembrane attackporeformation.InAIM2,wewillcomparetheroleandactivationmechanismofgasderminAand gasderminDinthemousemodelofbullouspemphigoidusingmicedeficientingasderminAandgasderminD intheinvivomodelofbullouspemphigoid,andbyreconstitutinggasderminactivationpathwaysinvitro. Thisgrantissignificantbecauseitwillprovidefoundationalknowledgethatmayaidinthedevelopment ofnoveltherapeuticsthattargetinflammasomesandgasderminstotreatbullouspemphigoid.Furthermore, thisgrantwillmorebroadlyprovideinsightsintothefunctionsofkeratinocytesasactiveparticipantsofinnate immunityandgasderminsasmediatorsofinflammationintheskin.Notably,toourknowledge,thiswouldbe thefirstin-depthcharacterizationofgasderminAasamediatorofskininflammation.Thus,insightsgained fromthisgrantmayimproveourunderstandingofthepathogenesisofbullouspemphigoidandother inflammatoryconditionsoftheskinaswellasourunderstandingofhowtheskinprotectsagainstinfection.